To improve recovery for individuals with SCI, gains in design and implementation of rehabilitation interventions are needed. Identifying cellular and molecular factors that impede the benefits of exercise training is an important first step. Understanding how these factors impact when rehabilitation should be initiated is also unknown. Therefore, using experimental SCI models, this proposal will explore the role of inflammation in spinal cord regions well-away from the SCI where movement is organized. The optimal window for skill training may be defined by these inflammatory mechanisms (Aim 1). We will use downhill treadmill training as it is more challenging than standard flat treadmill training. By initiating downhill training at different stages of inflammation, we will measure which stage training restores more locomotor recovery. Additionally, we will determine if activity-based training drives myelin changes along spared axons and improves function (Aim 2). These innovative studies use new transgenic technologies alongside clinically-relevant MRI approaches. Lastly, we will explore the regional differences in susceptibility to inflammation across the spinal cord (Aim 3). We may identify cord regions with high potential for training-induced recovery. Developing new types of training specifically for these pro-recovery regions may also boost functional recovery. The proposed studies have translational potential for human SCI.